April 29, 2013

Opportunities to Revolutionise Care in DevelopingCountries

This report provides an overview on the current state of play and a framework for action with regards to hepatitis C diagnostics and treatment in resource-poor settings.

SUMMARY AND STATEMENT OF PRIORITY

Hepatitis C (HCV) has been a silent killer among people living in low- and middle-income countries. Factors including lack of epidemiologic data, poorly tolerated treatment with low success rates, and cost and complexity of care have all contributed to a vicious cycle of neglect that has allowed a growing epidemic of HCV to blossom unchecked.

But recent advances in both diagnosis and treatment, as well as new data on prevalence in low- and middle-income countries, provides an unprecedented opportunity to take the lead in turning back the growing tide of HCV and dramatically improve the wellbeing of people infected with HCV. New all-oral regimens offer the potential of being robust, well-tolerated and pan-genotypic.

Thus, not only improving cure rates, but also simplifying diagnosis and management requirements. Advances in and scale up of molecular testing in low-resource environments facilitates diagnosis and monitoring of HCV.

Taken together, these new tools open the door to managing this deadly coinfection in low- and middle-income countries. The simplified package of care may also enable decentralization of diagnosis and treatment as well as pave the way for eventual task-shifting to less specialized cadres of health workers. However, several key interventions are required in order to spark this revolution in HCV care:

• Proactive normative guidelines at the WHO and at country level are needed • Regular screening of patients at high risk for HCV, including those infected with HIV, is critical • Access to appropriate diagnostics, including molecular tests, is of utmost importance and can be facilitated by utilizing the same platforms currently being rolled out for HIV • Prices of both interferon-based therapy as well as new all-oral therapy must be appropriate to facilitate scale up in low- and middle-income countries, and biosimilar and generic competition is required in order to reach a fair price. • Access to new oral therapies depends not only on price but also on registering of these new medications in key countries, as well as the WHO or other normative bodies signaling their importance by inclusion in the model Essential Medicines List.

There is no time like the present to rapidly address this hidden and ignored epidemic. The benefits of new tools and data will not be realised without key market interventions as well as prioritisation of this disease at the WHO and at country level. But if the choice is made to invest now in the tools needed to fight HCV in low- and middle-income countries, the potential benefits are vast.

CHICAGO (Reuters) - An influential panel is calling for HIV screening for all Americans aged 15 to 65, regardless of whether they are considered to be at high risk, a change that may help lift some of the stigma associated with HIV testing.

The new guidelines from the Preventive Services Task Force (USPSTF), a government-backed panel of doctors and scientists, now align with longstanding recommendations by the Centers for Disease Control and Prevention for testing of all adults aged 15 to 65, regardless of their risk.

Prior guidelines issued by the USPSTF in 2005 had recommended HIV screening for high-risk individuals.

Experts said the guideline change, published on Monday in the Annals of Internal Medicine, will likely trigger coverage for the tests as a preventive service under the Affordable Care Act. Under President Barack Obama's healthcare law, insurers are required to cover preventive services that are recommended by the task force.

Currently, the healthcare law recommends coverage of HIV testing for adolescents and adults who are at higher risk of infection.

"That was based on the 2005 USPSTF recommendations," Dr. Jeffrey Lennox, a professor of medicine at Emory University School of Medicine and chief of infectious disease at Grady Memorial Hospital, an inner-city hospital in Atlanta.

"Now, hopefully they will go back and re-categorize that and recommend that it will be covered for every adult."

A spokeswoman for the U.S. Department of Health and Human Services could not confirm the tests would be covered, but Lennox said it may take a while before the agency catches up to the new policy.

Abstract and Introduction

Abstract

Rapid testing for HCV has become a routine practice in resource-limited settings for initial screening. The objective of this study was to evaluate the performance of rapid immunoassay diagnostic test kits for specific and accurate diagnosis of HCV infection among different patient groups in clinical settings of Kolkata, India. Two hundred and fifty-four randomly selected serum samples of 612 samples reported as HCV nonreactive by rapid immunodiagnostic tests were evaluated for HCV antibody, ELISA and HCV RNA testing for confirmatory diagnosis. 15.74% were HCV seropositive by ELISA, and 11.02% were RNA positive by nested RT-PCR. Additionally, 15 HCV-seronegative chronic liver disease patients with high ALT and AST values were screened for HCV RNA, of which five were positive whose viral load ranged from 1.2 × 102 to 4.4 × 106 IU/mL, and the samples belonged to IVDUs and HIV-co-infected individuals. The results showed that HCV rapid immunoassay test cannot be solely relied on as an absolute and accurate diagnostic tool for screening infection of HCV particularly in high-risk group patients such as IVDUs, haemodialysis, thalassaemic and HIV-co-infected patients who need HCV screening frequently.

Introduction

Hepatitis C virus (HCV) infection is a global health problem affecting around 170 million people worldwide and is a leading cause of liver cirrhosis and hepatocellular carcinoma.[1] In India, HCV infection as a cause of acute viral hepatitis has been reported to vary between 0–21% and responsible for 14–26% cases of chronic liver disease.[1] HCV infection is mostly acquired through transfusion of blood or blood products. A high prevalence of HCV is found in many high-risk groups (HRG) exposed to blood or blood products, like intravenous drug users (IVDUs), patients with paediatric haematologic malignancies and those with thalassaemia and haemophilia. The prevalence of HCV in blood donors in India (1–1.5%) is higher than that in developed countries.[2]

The laboratory diagnosis of HCV infection is based on the detection of circulating antibodies and viral RNA. The most widely used HCV screening tests are ELISA and HCV RNA by nucleic acid test (NAT), as they are the most appropriate for screening large numbers of specimens on a daily basis.[3] These assays are technically demanding and require sophisticated laboratory infrastructure. Hence, in developing countries like India, the blood transfusion centres mostly rely on simple, rapid tests for HCV with individual kits as an inexpensive alternative for ELISA or NAT assays. Although the use of simple rapid immunoassays has significantly reduced the risk of HCV transmission, the window period for the detection of recent or new infection among the high-risk group remains a concern. The purpose of our study was to determine the performance of simple rapid immunoassay in patients who belonged to high-risk group such as thalassaemic and haemodialysis patients, who undergo blood transfusions regularly. As no previous literature is available on the contradictory results of the HCV rapid immunoassay, our study aimed to help the clinicians and the laboratory personnel on false-negative results of the rapid immunoassay, so that in future more confirmatory screening tests would be employed in blood transfusion centres to detect accurately the status of the HCV-positive patients.

Material and Methods

Clinical Samples

Blood samples were collected from different liver clinics, haemodialysis centres, HIV Apex Clinic and thalassaemic patients from Kolkata between March 2006 and February 2011. Among the 612 samples received during this period, 254 samples that were hepatitis B and HCV rapid immunoassay nonreactive but having increased levels of AST and ALT in patients with chronic liver diseases were included in this study. This was an IEC-approved study, and informed consent was obtained from the individuals during the collection of blood samples.

Detection of HCV Antibody by Rapid Immunoassay and ELISA

Rapid diagnosis of HCV was performed using fourth-generation HCV TRI-DOT (WHO-GMP certified, sensitivity 100% and specificity 98.9%; J. Mitra, New Delhi, India), as well as with Signal HCV Kit (sensitivity 98% and specificity 99.45%; Span Diagnostics Ltd, Surat, India).[4] The same sets of samples were tested for the presence of antibodies against HCV core, NS3 and NS5 regions using two commercially available ELISA kits Hepanostika anti-HCV Ultra Kit (Biomerieux, Boxtel, The Netherlands) and HCV Microlisa (J. Mitra) to verify the results. The fourth-generation HCV TRI-DOT utilizes a unique combination of modified HCV antigens conserved across all genotypes from the putative core, NS3, NS4 and NS5 regions of the virus to selectively identify all genotypes of HCV in human serum/plasma with a high degree of sensitivity and specificity.

Detection and Quantitative Estimation of HCV RNA

The viral RNA was extracted using QIAamp viral RNA mini kit (QIAGEN, Hilden, Germany) according to the manufacturer's protocol. HCV viral RNA was detected by nested RT-PCR based on 5' noncoding region (5' NCR) of HCV genome according to Saha et al..[5] Briefly, the first-round RT-PCR was performed in 20-μL total reaction volume containing 2 μL of isolated RNA with outer forward primer (PS1) 5'-ACTGTCTTCACGCAGAAAGCGTCTAGCCAT-3' and outer reverse primer (PA1) 5'-CGAGACCTCCCGGGGCACTCGCAAGCACCC-3'. The second-round nested PCR was performed with inner forward primer (PS2) 5'-ACGCAGAAAGCGTCTAGCCATGGCGTTAGT-3' and inner reverse primer (PA2) 5'-TCCCGGGGCACTCGCAAGCACCCTATCAGG-3'. The primers were selected/used in this nested RT-PCR from highly conserved domains within the 5' NCR region of the HCV genome according to Bukh et al.,[6] which is well conserved across all the six HCV genotypes. A positive band at 256 bp in 1.5% agarose gel stained with ethidium bromide was observed in gel documentation system (Bio-Rad Laboratories, Hercules, CA, USA) for HCV RNA-positive samples. Quantitative hepatitis C viral RNA was determined using ABI real time RT-PCR kit (AgPath-IDTM One-Step RT-PCR kit, Applied Biosystems, Foster City, CA, USA). The HCV primer and probe sequences were directed against the 5' noncoding region of the HCV genome.

DNA Sequencing and Genotyping

Nested RT-PCR-amplified 256-bp amplicon of 5' NCR of HCV genome was gel-purified and directly used for DNA sequencing analysis in an automated DNA Sequencer, model 3130XL (Applied Biosystems) using Big Dye terminator 3.1 kit (Applied Biosystems). The genotypes of the sequences obtained were determined using the NCBI genotyping tool.[7]

Statistical Analysis

Mean and median values were calculated. The P-values ≤ 0.05 were considered statistically significant.

Results and Discussion

The study involved 612 patients who were screened for HCV infection using rapid immunoassay kits. Seventy-nine per cent of the patients belonged to 40–60 age group, of which 74% of the patients were men and 26% women.

All serum samples selected in this study were evaluated using two different rapid HCV immunodetection kits, namely TRI-DOT and Signal HCV. Of the total 612 samples, 254 (41.50%) reported as HCV nonreactive were screened for this study. Furthermore, of the 254 samples, 40 (15.74%) were seroreactive by both the ELISA methods. All the seropositive samples were screened for HCV RNA detection; among them, 28 (70%) were HCV RNA positive.

Fifteen-ELISA-nonreactive samples from HRG with a history of chronic liver disease and high AST and ALT values were processed for HCV RNA detection. Five samples were HCV RNA positive, of which three were IVDUs and other two were HIV-co-infected patients with a history of surgery and blood transfusion (). All these HCV RNA-positive samples were further processed for viral quantitation and genotyping. It was found that the viral load ranged from 1.2 × 102 to 4.4 × 106 IU/mL and four were genotype 3, whereas one was genotype 1 (). The median ALT value was calculated at 45 IU/mL (min. 15.55, max. 111.32 IU/mL) and AST at 109.63 IU/mL, respectively (min. 60.23, max. 293.36 IU/mL) (Table 1).

From our results, we could surmise that HCV rapid immunoassay gave false-negative results in patients belonging to high-risk group especially in IVDUs, haemodialysis, thalassaemic, and HIV-co-infected patients. 11.02% of samples marked as rapid immunoassay nonreactive were in fact HCV RNA positive as determined by NAT (HCV RNA) assays. Results obtained were compared by additionally testing the samples using ELISAs and NAT. Two different ELISA kits were used to compare the specificity of the results. Forty (15.74%) samples were seropositive by both the HCV ELISA kits. In addition, the findings showed that of 15 ELISA-seronegative samples, five were HCV RNA positive, that is, the patients were active carriers of the HCV infection. All the seronegative samples that were HCV RNA positive belonged to patients in high-risk group. One of the striking observations was that even though these patients were asymptomatic and declared as HCV nonreactive by rapid immunoassay, they had high levels of ALT and AST values that indicated a dysfunction in their liver.

Our genotyping data showed that of the HCV RNA-positive patients, 80% were infected with genotype 3. The viral load in patients with genotype 3 was significantly lower than in those infected with genotype 1. Diagnosis of HCV in these cases is difficult, as these patients cannot produce sufficient anti-HCV antibodies because of immunosuppression.[8] Additionally, false-negative results could be attributed to genetic heterogeneity, which could affect the serological response. The most prevalent HCV strain in India is genotype 3,[9] which is a slow-growing variant, and therefore, the probability of false negatives for this genotype may increase in rapid immunoassay tests. Although HCV rapid immunoassays are routinely used in practically all laboratories, our results showed for the first time that many of the samples declared as HCV rapid immunoassay nonreactive in initial screening were in fact HCV RNA positive, that is, the patients were active carriers of the infection. This shows that rapid tests might give false-negative results particularly for patients belonging to HRG. Missing positivity in immunoassays occurs mainly in immunocompromised patients who fail to clear away the antigens or in patients with autoimmune disorders, hyperglobulinemia or in low-risk blood donors who donate blood frequently. In these cases, confirmatory HCV tests by nucleic acid amplification test (NAT) assays remain the method of choice. The presence of HCV RNA in a patient's serum confirms the active state of infection.

To conclude, the present study highlights that HCV rapid immunoassay tests should not relied upon as the sole criterion for screening patients in high-risk group. In these cases, confirmatory methods should be deployed for HCV detection, so that the rate of false-negative results can be scaled down, and the patients can be effectively screened and put on medication as soon as possible. Although this study is in a preliminary stage, it aims to provide useful inputs to scientific community and the policy makers to improve the existing infrastructure in screening patients for HCV.

In early results from an observational cohort, about two-thirds of evaluable patients had undetectable virus 4 weeks after the end of therapy with pegylated interferon and ribavirin along with a protease inhibitor, according to Elizabeth Verna, MD, of Columbia University in New York City.

But that must be "balanced" against a high rate of adverse events, including need for hospital admission, kidney dysfunction, and death, Verna reported at the meeting of the European Association for the Study of the Liver.

Treatment with pegylated interferon and ribavirin has been shown to lead to sustained virologic responses in about 30% of patients with the hard-to-treat genotype 1 of the virus, Verna noted.

And adding one of the recently approved protease inhibitors – telaprevir (Incivek) or boceprevir (Victrelis) – improves the odds, she said.

But triple therapy has not been tested in transplant patients whose genotype 1 virus recurs, usually in a very aggressive fashion. To help fill the gap, she and colleagues are following 112 patients receiving triple therapy at six U.S. centers.

Of those, she noted, 15 had been on pegylated interferon and ribavirin for more than 90 days before the protease inhibitors were approved in mid-2011 and they could be started on the new drugs.

Those patients were excluded from efficacy analyses, but included in safety studies.

The other 97 patients had a short lead-in period with interferon and ribavirin, followed by triple therapy (with telaprevir in most cases), and then took interferon and ribavirin again, for a total of 48 weeks.

Verna presented efficacy data at the EASL meeting on a subset of 43 patients who have completed therapy and had at least 4 weeks of observation afterward. Most remaining patients are still on interferon/ribavirin.

Verna said that 63% of those patients had what she called an extended rapid virologic response, defined as undetectable HCV viremia 4 and 12 weeks after the start of triple therapy.

At the end of therapy, 67% had undetectable viremia, and 4 weeks later the rate was 65%.

Currently, in the era of triple therapy and a host of investigational direct-acting HCV drugs, undetectable viremia 12 weeks after the end of therapy is regarded as tantamount to a cure.

While the early efficacy results are promising, Verna said 11% of the cohort had adverse events that led to stopping treatment, 21% needed to be admitted to hospital, 34% needed transfusions, 4% suffered graft rejection, and 6% died (4% from liver-related causes).

The study is an important step forward, although the results remain preliminary, commented Patrizia Burra, MD, PhD, of Padova University Hospital in Padua, Italy, who was not involved in the study but who moderated an EASL session at which it was presented.

At a minimum, the investigators have "demonstrated that [triple therapy] can be used quite safely," she told MedPage Today. She noted that high rates of adverse events are to be expected in these patients, many of whom have aggressive disease.

Also the preliminary efficacy data are encouraging, she said, and suggest it may be possible to rescue HCV patients who relapse after transplant. "We're really hoping to see good results," she said.

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania

AMSTERDAM – A four-drug regimen was effective in hard-to-treat hepatitis C (HCV) patients who had previously failed therapy, a researcher said here, but the drug combination is not being further developed.

In a phase II study, 70% of patients had undetectable HCV virus 12 weeks after ending the so-called "quad regimen," according to Gregory Everson, MD, of the University of Colorado in Aurora.

The drug protocol consisted of an NS5A inhibitor dubbed ledipasvir and a protease inhibitor, GS-9451, along with pegylated interferon and ribavirin.

Among those who responded to the four-drug regimen quickly and persistently, the rate was even higher at 87%, Everson reported at the meeting of the European Association for the Study of the Liver.

But despite the promise of what he called a "re-treatment protocol," Everson said further development of the regimen is not in the cards.

He did not immediately respond to an email from MedPage Today seeking clarification, but other experts here suggest it may have to do with the perception that pegylated interferon and ribavirin are on the way out.

Meanwhile, ledipasvir and GS-9451 remain in clinical development, according to a spokesman for the developer, Gilead Sciences of Forest City, Calif.

The results of the trial "are not entirely unexpected," commented Heiner Wedemeyer, MD, of Hannover Medical School in Hannover, Germany, who was not involved with the study.

"This specific regimen is not being further developed," he said, but what investigators "learned is that if we add more potent drugs, we can treat more difficult patients. We confirmed that concept."

It seems likely, he said, that the two drugs will continue to be developed for use without interferon and perhaps ribavirin. "The question will be whether we can shorten treatment," Wedemeyer said.

Until 2011, standard therapy for HCV genotype 1 was 48 weeks of pegylated interferon with ribavirin, a regimen regarded as difficult to tolerate with a substantial proportion of treatment failures.

Current standard therapy adds a third drug, one of the protease inhibitors telaprevir (Incivek) or boceprevir (Victrelis), but those medications have their own side effects and risks.

Patients who fail standard treatment – either relapsing or not responding in the first place – need better options, Everson said here.

He and colleagues tested the four drugs (ledipasvir, GS-9451, pegylated interferon, and ribavirin) in a response-guided fashion, enrolling 163 patients, including 52 who had not responded to previous therapy, 28 who had a partial response, and 83 who either relapsed or had viral breakthrough on treatment.

Patients who had undetectable viral RNA at weeks four through 20 of treatment stopped therapy after 24 weeks, while the others stopped ledipasvir and GS-9451 but continued the other two drugs for another 24 weeks.

The 70% rate of undetectable virus 12 weeks after the end of therapy (SVR12) indicated a "fairly robust antiviral effect," Everson said, and response during therapy was "highly predictive " of treatment success.

Among those who had a so-called extended rapid virologic response – no detectable virus from weeks four through 20 – the SVR12 rate was 87%, compared with just 28% among those who did not have such a response.

Everson said that patients with genotype 1b did better than those with genotype 1a, while those with the favorable CC variant of the IL-28B gene did better than those with other versions.

He added that 5% of patients had a serious adverse event during the study and 7.3% stopped treatment because of adverse events, all attributed to the interferon or ribavirin.

The overall pattern of adverse events, he said, was "typical" of what is seen with the two older drugs.

The study was supported by Gilead. Everson reported financial links with the company as well as BMS, Abbott, Roche/Genentech, Vertex, Merck/Schering-Plough Novartis, Janssen/Tibotec, GSK, Eisai, and BioTest.

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania

AMSTERDAM -- High levels of hemoglobin may be dangerous in patients with nonalcoholic fatty liver disease (NAFLD), with bleeding a potential remedy, researchers said here.

NAFLD patients undergoing periodic phlebotomy for 2 years in an open-label, randomized trial showed significant declines in alanine and aspartate aminotransferase (ALT, AST) levels and improvements in liver tissue histology relative to an untreated control group, according to Luca Valenti, MD, of the University of Milan in Italy, and colleagues.

And, in a separate study led by Angela Peltec, MD, of the University of Medicine and Pharmacy in Kishinev, Moldova, NAFLD patients in the highest quartile of hemoglobin (more than 152 g/L) had significantly poorer cardiovascular risk profiles than those in the lowest (less than 128.5 g/L).

The Moldovan group found that patients in the highest hemoglobin quintile had a mean 10-year probability of a major cardiovascular event of 28% according to the Framingham equation, compared with 4% in the lowest quartile (P<0.05).

Both studies were reported at the European Association for the Study of the Liver's annual meeting.

Previous studies have found that NAFLD patients are prone to show a degree of iron overload, Valenti and colleagues noted. Some research has linked hemoglobin levels to the level of liver damage in NAFLD patients, as well as suggesting that excess iron may be overtly hepatotoxic -- that is, not just an epiphenomenon in NAFLD.

A pilot clinical study led by Valenti in 2011 found that phlebotomy reduced serum transaminase levels, prompting the group to conduct a larger, randomized trial.

The Italian researchers recruited 38 patients with iron overload, defined as serum ferritin higher than 250 mg/mL or on the basis of liver histological analysis and blood hemoglobin of more than 11 g/dL. They were randomized either to no iron-directed treatment or to phlebotomy every 2 weeks, with 350 mL of blood taken at each session, until serum ferritin declined to less than 100 mg/mL and transferrin saturation was in the range of 40% to 50%.

All patients also underwent lifestyle counseling as usually provided to NAFLD patients in the Milan clinic.

Heavy drinkers, the severely obese, and patients with hereditary hemochromatosis or non-NAFLD liver diseases were excluded.

Control patients showed slight average declines from baseline in serum ferritin and transferrin saturation, whereas those undergoing phlebotomy had markedly steeper reductions.

At the 2-year evaluation, mean ferritin levels stood at about 600 mg/mL in the control group compared with less than 200 mg/mL in the phlebotomy arm (P<0.005). Similarly, mean transferrin saturation was about 38% in controls versus 28% in the phlebotomy group after 2 years (P<0.05); at baseline, both groups had averages close to 40%.

Both groups had dips in mean ALT and AST levels at the 6-month mark, but levels plateaued or increased in the control group at subsequent evaluations, whereas they continued to decline in the phlebotomy group.

At the 2-year measurement, mean ALT and AST levels in controls were 37 and 28 IU/mL, respectively, compared with 24 and 21 IU/mL in the phlebotomy group (both P<0.05 relative to control), Valenti and colleagues reported.

Also, histologic analysis of liver biopsy samples indicated that 33% of the phlebotomy patients and 11% of the controls (P<0.05) had improvements from baseline during the study period.

There were no significant differences between groups in weight loss or changes in waist circumference.

The Moldovan study was a cross-sectional analysis of 117 NAFLD patients, with data collected for cardiovascular risk prediction according to the Framingham system as well as measurements of blood hemoglobin content.

After adjusting for known cardiovascular risk factors, the odds ratio for having a Framingham risk rated as high (greater than 20%) was 3.45 for the highest versus lowest quartile (95% CI 1.12 to 10.70). For patients in the third quartile (hemoglobin of 140 to 152 g/L), the adjusted odds ratio for high cardiovascular risk was 2.07 (95% CI 1.68 to 10.97) versus the lowest quartile.

High hemoglobin levels were associated with younger patient age, higher blood lipid levels, and increased ALT and AST, Peltec and colleagues reported. But the prevalence of hypertension and type 2 diabetes did not correlate significantly with hemoglobin, nor did body mass index values.

Peltec and colleagues concluded that hemoglobin measurement could be helpful in gauging cardiovascular risk in NAFLD patients, in addition to traditional risk factors.

The Moldovan study was limited by its cross-sectional nature and relatively small enrollment. The study by Valenti and colleagues also had relatively few patients. Neither study used actual clinical outcomes.

Neither study had commercial funding.

Valenti and Peltec reported that they had no relevant financial interests.

- Galectin Therapeutics and Icahn School of Medicine at Mount Sinai Data Presented at the International Liver Congress 2013 -

NORCROSS, Ga., April 29, 2013 /PRNewswire/ -- Galectin Therapeutics (NASDAQ: GALT), the leading developer of therapeutics that target galectin proteins to treat fibrosis and cancer, today released data that was presented on April 27, 2013 at the International Liver Congress in Amsterdam, The Netherlands. The data were generated by the laboratory of Dr. Scott Friedman of the Icahn School of Medicine at Mount Sinai, a world renowned investigator and expert on liver fibrosis. GR-MD-02 and GM-CT-01, drugs that inhibit galectin proteins, were found to reverse the most advanced stage of liver fibrosis, called cirrhosis, in experimental animals given toxin-induced cirrhosis.

"The findings of these experiments show that the anti-galectin drugs had a robust effect on cirrhosis, including reversal of tissue architectural changes in the liver that result from fibrosis as well as reduction in portal hypertension, an important pathophysiological effect of cirrhosis," said Dr. Friedman, Dean for Therapeutic Discovery and Chief, Division of Liver Diseases at the Icahn School of Medicine at Mount Sinai. "The experimental design of these studies provided a very high hurdle for any drug to show effectiveness, and yet both GR-MD-02 and GM-CT-01 passed the test. These drugs are excellent candidates for evaluation in human cirrhosis."

"We are gratified that one of the most prominent investigators in the world has shown that our galectin inhibitors were effective in experimental cirrhosis, the most severe form of liver fibrosis, for which there are no currently approved medical therapies," said Dr. Peter G. Traber, President, Chief Executive Officer and Chief Medical Officer, Galectin Therapeutics. "Along with the multiple studies we have presented on liver fibrosis from fatty liver disease, these findings provide added confidence for the potential of this approach in studies of human liver fibrosis and cirrhosis."

The data presented at the International Liver Congress which is sponsored by the European Association for the Study of the Liver (EASL) are posted on the Company website at http://bit.ly/14xDpKK. Rats were treated with a liver toxin which produced fibrosis that replaced over 25% of the liver tissue and resulted in architectural changes consistent with cirrhosis. While continuing to treat with the liver toxin, rats were treated with either a placebo or four weekly injections of either GR-MD-02 or GM-CT-01. The livers were reviewed by a highly qualified liver pathologist who was unaware of the treatments that the animals had received. Both drugs significantly reduced the amount of fibrotic tissue, and most importantly, reversed the histological findings of cirrhosis. Additionally there was a reduction in the blood pressure in the blood system supplying the liver (portal pressure) in the treated animals. Cirrhosis and portal hypertension are the primary abnormalities that lead to complications and death in humans with liver fibrosis. Galectin previously announced initiation of a Phase 1 clinical trial of GR-MD-02 in patients with fatty liver disease (NASH, non-alcoholic steatohepatitis) with advanced fibrosis which is expected to begin enrolling patients in May 2013 (http://bit.ly/11wj6hr).

About Galectin TherapeuticsGalectin Therapeutics (NASDAQ: GALT) is developing promising carbohydrate-based therapies for the treatment of fibrotic liver disease and cancer based on the Company's unique understanding of galectin proteins, key mediators of biologic function. We are leveraging extensive scientific and development expertise as well as established relationships with external sources to achieve cost effective and efficient development. We are pursuing a clear development pathway to clinical enhancement and commercialization for our lead compounds in liver fibrosis and cancer. Additional information is available at www.galectintherapeutics.com.

Forward Looking StatementsThis press release contains, in addition to historical information, forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These statements relate to future events or future financial performance, and use words such as "may," "estimate," "could," "expect" and others. They are based on our current expectations and are subject to factors and uncertainties which could cause actual results to differ materially from those described in the statements. Factors that could cause our actual performance to differ materially from those discussed in the forward-looking statements include, among others: incurrence of operating losses since our inception, uncertainty as to adequate financing of our operations, extensive and costly regulatory oversight that could restrict or prevent product commercialization, inability to achieve commercial product acceptance, inability to protect our intellectual property, dependence on strategic partnerships, product competition, and others stated in risk factors contained in our SEC filings. We cannot assure that we have identified all risks or that others may emerge which we do not anticipate. You should not place undue reliance on forward-looking statements. Although subsequent events may cause our views to change, we disclaim any obligation to update forward-looking statements.

Transgene SA (Paris:TNG) (Euronext Paris: FR0005175080), a biopharmaceutical company that develops targeted immunotherapy products to treat major unmet medical needs in cancer and chronic infectious diseases, announced final data of the Phase 2 HCVac trial of TG4040 for the treatment of genotype 1 chronic hepatitis C (CHC) at an oral presentation of the European Association for the Study of the Liver (EASL) Congress in Amsterdam, the Netherlands.

Professor Heiner Wedemeyer, University of Hanover, Germany and Principal Investigator of the HCVac trial, today presented the final data at EASL and stated: “This trial is unique in the field of hepatitis C, representing one of the largest randomized studies ever investigating an immunotherapeutic product against a persistent infection. It is remarkable that TG4040 induced a decline in HCV viral load and that early response rates of standard therapy with peg-interferon alpha and ribavirin were increased. In addition, very important general findings were made that will help Transgene optimize the future clinical development of TG4040.”

The positive effect of TG4040 was seen with pre-treatment of TG4040 in Arm C. The benefit of pre-treatment was observed as early as one week after initiation of PEG-IFNα/RBV with a 40% improvement in decline of mean HCV RNA viral load. The primary endpoint was met in Arm C with a complete early viral response (cEVR) of 64% as compared to 30% in the control arm (p=0.0037).

The virologic response was sustained over time with a SVR24 of 58% in Arm C, compared to 48% in the control arm.

The key immunologic findings were that induction of MVA and HCV specific T-cell responses were essentially seen in Arm C before the addition of PEG-IFNα/RBV. The viral response seen in Arm C was observed in spite of the development of anti-MVA responses.

Overall, safety was similar across the three arms (percentage of adverse events and grade). The investigation of the four cases of severe blood toxicity led to the conclusion of an exacerbation of IFN-known immune side effects in patients with autoimmune predisposition (see press release of 23rd April 2012).

Philippe Archinard, Chairman and Chief Executive Officer of Transgene, stated: “Today’s oral presentation at EASL once again verifies the high level of scientific and medical interest in Transgene’s immunotherapy products. The final results of the HCVac study demonstrated that a specific vectored immunotherapeutic can improve treatment of CHC. While new treatment paradigms are currently emerging, and are likely to enter the market as early as 2014, Transgene is examining different opportunities for TG4040’s future clinical development. Given the results of our Phase 2 study, immunotherapy with TG4040 may warrant further evaluation in combination with IFN-free direct-acting antivirals treatment regimens once they are approved.”

About TG4040

Transgene’s TG4040 immunotherapeutic product is a recombinant vector based on the MVA virus carrying and expressing three of the major non-structural proteins (NS3, NS4 and NS5B) of the hepatitis C virus (“HCV”). The MVA vector is a highly attenuated strain of vaccinia virus, which has been tested extensively in humans as a vaccine against smallpox and is known to strongly stimulate innate and adaptive immune responses to antigens.

About TG4040 Clinical Development Program

In this Phase 2 HCVac study, a total of 153 treatment-naïve patients were enrolled in 28 sites from Europe, the United States and Israel. Patients were randomized in three arms: one control arm (48 weeks of Peg-IFN/RBV) or one of the two experimental arms. In one experimental arm, the TG4040 dosage (subcutaneous injections at the dose of 107 pfu) was administered six times and Peg-IFN/RBV was given as a 4 week lead-in prior to the initiation of TG4040. In the other experimental arm, the same TG4040 dosage was administered 13 times and Peg-IFN/RBV was introduced twelve weeks after initiation of pre-treatment with TG4040. The HCVac trial evaluated the efficacy and safety of these two different schedules of TG4040 administration in combination with Peg-IFN and RBV as compared to Peg-IFN/RBV alone.

About Transgene

Transgene (NYSE-Euronext: TNG), a member of the Institut Mérieux Group, is a biopharmaceutical company. We create, develop and manufacture targeted immunotherapeutics for the treatment of cancers and infectious diseases. Our products are major technological breakthroughs that use well tolerated viruses to indirectly or directly kill infected or cancerous cells. Our four most advanced products have generated proof of concept data in randomized clinical studies: in lung cancer (TG4010), liver cancer (Pexa-Vec), hepatitis C (TG4040) and HPV-related cervical lesions (TG4001). We have concluded strategic agreements for the development of three of these products: an option agreement with Novartis for the development of TG4010, an in-licensing agreement with US-based Jennerex, Inc. to develop and market Pexa-Vec and a strategic collaboration with EORTC to develop TG4001 in cancer of the oropharynx. We also have a non-exclusive agreement with Sanofi/Genzyme for the future commercial production of our products. Most of our 280 employees are based in Strasbourg, France, and we have operations in Lyon, China and the USA. Additional information about Transgene is available at www.transgene.fr.

Transgene Forward Looking Statements

This press release contains forward-looking statements notably referring to plans for the future development of TG4040 as a treatment against chronic hepatitis C, in combination with new treatments. These plans are subject to changes and uncertainties and we could never be able to develop, manufacture or sell TG4040 in the future. For further information on the risks and uncertainties involved in the testing and development of Transgene’s product candidates, see Trangene’s Document de Référence on file with the French Autorité des marchés financiers on its website at http://www.amf-france.org and on Transgene’s website at www.transgene.fr.

The addition of faldaprevir to pegylated interferon/ribavirin therapy significantly improved rates of sustained virologic response and allowed for shorter treatment duration among patients with chronic hepatitis C in a study presented at the International Liver Congress in Amsterdam.

In the STARTVerso1 study, patients with chronic HCV genotype 1 received 48 weeks of therapy with peginterferon alfa-2a and ribavirin (PEG/RBV) and were randomly assigned either placebo (n=132) for 24 weeks, 120 mg faldaprevir (FDV, Boehringer Ingelheim Pharmaceuticals) (n=259) for 12 or 24 weeks, or 240 mg FDV (n=261) for 12 weeks. HCV RNA below 25 IU/mL after 4 weeks and undetectable RNA at 8 weeks were considered early success among treated patients, and therapy, including PEG/RBV, was stopped at 24 weeks.

Sustained virologic response (SVR) at 12 weeks occurred in more 120-mg (79%) and 240-mg (80%) treated patients than placebo participants (52%, P<.0001). Treatment was stopped at 24 weeks due to early response in 87% and 89% of the 120-mg and 240-mg groups, respectively, compared with 22% of placebo recipients. Among those who stopped treatment early, SVR12 was achieved by 86% of the 120-mg group, 89% of the 240-mg group and 90% of placebo patients.

Serious adverse events occurred at similar rates (6% of placebo recipients; 7% of treated groups), as did treatment discontinuation due to adverse events (4% of the placebo and 120-mg groups; 5% of the 240-mg group). Discontinuation of FDV, but not PEG/RBV, due to adverse events occurred in 1% of the 120-mg group and 3% of the 240-mg group. Anemia, rash and GI issues were reported most commonly.

“Faldaprevir has shown efficacy in a range of genotype-1a and 1b HCV patients with and without cirrhosis,” researcher Peter Ferenci, MD, Medical University of Vienna, said in a press release. “The viral cure rates and potential for shorter treatment duration seen in STARTVerso1 are very encouraging for the many patients currently facing a year of interferon-based treatment.”

Transgene SA /quotes/zigman/211949 FR:TNG +2.73% (euronext paris:FR0005175080), a biopharmaceutical company that develops targeted immunotherapy products to treat major unmet medical needs in cancer and chronic infectious diseases, announced pre-clinical data obtained with its novel immunotherapeutic, TG1050, to treat chronic hepatitis B infection (CHB). These results were presented in an oral session (Hepatitis B and D Experimental) at this year's European Association for the Study of the Liver Conference (Amsterdam, Netherlands, April 24-28, 2013).

Philippe Archinard, Chairman and Chief Executive Officer of Transgene, stated: "We are excited that TG1050 was selected for an oral presentation at EASL. We hope that this presentation will trigger interest in the scientific community as well as discussions with potential partners. We expect to start a first-in-human/phase 1 clinical trial in 2014 and we believe that TG1050 is currently the most promising direct active immunotherapeutic in development for the treatment of CHB, an area of unmet medical need and high worldwide prevalence."

The selection process from 32 promising product candidates of TG1050 was endorsed and approved by different panels of key opinion leaders in the viral hepatitis field. TG1050 is based on a non-replicative Adenovirus 5 vector that encodes three HBV (Hepatitis B Virus) antigens or related domains. The clinical candidate has demonstrated potent immunogenicity in pre-clinical mouse models as well as genetic stability. Immunogenic properties include induction of potent, multi-specific, functional and cross-reactive T cell responses, including both cytokines production (IFN/TNFa) and in vivo cytolysis; all important characteristics that have been associated with viral clearance during natural infection.

Today's presentation provided updated and more recent data that demonstrated the capacity of TG1050 to induce long-lasting HBV-specific memory T cells. Experiments in two murine models based on hepatic expression of the full length HBV genome, a HBV transgenic mouse model (University of Ulm) and a model using a recombinant adenovirus associated virus encoding HBV (AAV-HBV, Institute Pasteur) showed that a single injection of TG1050 had the capacity to educate HBV-specific functional T cells within a tolerant environment without inducing liver inflammation, whilst displaying antiviral activities, which were particularly shown in the AAV model.

"TG1050 is to my knowledge the most comprehensive HBV immunotherapeutic currently under development that will be delivered by a single vector. Viral vectors and adenovirus-based vectors in particular, remain today the most efficient delivery platform when it comes to inducing strong cellular immune responses which play a central role in the control of HBV infection. A strong inverse correlation exists between HBV specific functional T-cells and control/eradication of viremia; immunotherapeutic for the treatment of CHB may provide a significant increased cure rate to the existing antiviral drugs" stated Dr Fabien Zoulim, Medical Director of the Liver Department at the Hospices Civils de Lyon and Scientific Director of the Hepatitis Research Laboratory at INSERM Unit 1052. He added further: "This type of approach provides new hope towards the development of a treatment with limited duration either alone or in combination with nucleoside analogues."

About TG1050

The novel immunotherapeutic product TG1050 developed by Transgene to treat chronic infection by hepatitis B is based on a recombinant non-replicative human adenovirus serotype 5, expressing multiple specific HBV antigens (Core, Polymerase and Envelope) from genotype D. The product has been designed to prime de novo and/or stimulate functional T cells expected to control the HBV replication and to elicit viral clearance.

According to the World Health Organization's ("WHO") estimates, 350 million people are chronic carriers (WHO, 2009) of HBV. Hepatitis B is more common in some parts of the world than others. In China and other parts of Asia, up to 10% of the population is believed to be chronically infected. In addition to the significant burden of disease, CHB is responsible for 1 million deaths each year due to related complications such as liver failure, cirrhosis or hepatocellular carcinoma (liver cancer).

About Transgene

Transgene (nyse-euronext:TNG), a member of the Institut Merieux Group, is a biopharmaceutical company. We create, develop and manufacture targeted immunotherapeutics for the treatment of cancers and infectious diseases. Our products are major technological breakthroughs that use well tolerated viruses to indirectly or directly kill infected or cancerous cells. Our four most advanced products have generated proof of concept data in randomized clinical studies: in lung cancer (TG4010), liver cancer (Pexa-Vec), hepatitis C (TG4040) and HPV-related cervical lesions (TG4001). We have concluded strategic agreements for the development of three of these products: an option agreement with Novartis for the development of TG4010, an in-licensing agreement with US-based Jennerex, Inc. to develop and market Pexa-Vec and a strategic collaboration with EORTC to develop TG4001 in cancer of the oropharynx. We also have a non-exclusive agreement with Sanofi/Genzyme for the future commercial production of our products. Most of our 280 employees are based in Strasbourg, France, and we have operations in Lyon, China and the USA. Additional information about Transgene is available at www.transgene.fr.

Transgene Forward Looking Statements

This press release contains forward-looking statements notably referring to the future development of TG1050 as a treatment against chronic hepatitis B. Such anticipated development is based on the results obtained in preclinical models. These results are not necessarily predictive of the results that we may obtain in future clinical testing on Man. We could never be able to develop, manufacture or sell TG1050 in the future. For further information on the risks and uncertainties involved in the testing and development of Transgene's product candidates, see Transgene's Document de Reference on file with the French Autorite des marches financiers on its website at http://www.amf-france.org and on Transgene's website at www.transgene.fr.

JERUSALEM, Apr 29, 2013 (BUSINESS WIRE) -- BioLineRx /quotes/zigman/5956062/quotes/nls/blrx BLRX -1.05% (tase:BLRX), a biopharmaceutical development company, announced today enrollment of the first patient in a Phase I/II trial for BL-8020, an orally available, interferon-free treatment for the Hepatitis C virus (HCV). The patient was enrolled at the Hopital Cochin in Paris, France.

The study is an open-label trial to evaluate the efficacy, safety and tolerability of BL-8020 in patients infected with HCV. It will be conducted at two clinical sites in France and will include up to 32 HCV-infected patients of any genotype who have previously failed or relapsed following treatment with the standard-of-care. BL-8020 is a proprietary fixed-dose combination treatment composed of Ribavirin and Hydroxychloroquine (HCQ), which results in an improved version of Ribavirin. The primary endpoint of the study is to evaluate the effect of a 16-week combination therapy with Ribavirin and HCQ. The study is specifically designed to allow intra-subject analysis, in order to determine the extent to which HCQ enhances Ribavirin's antiviral activity.

BL-8020 is an orally available HCV treatment with a unique mechanism of action that targets the host cell, and thus differs from other currently used anti-HCV agents. This suggests pan-genotypic efficacy and the ability to be combined with other HCV therapeutics as part of an interferon-free regimen. BL-8020's mechanism of action involves the inhibition of HCV-induced autophagy in the host cells. Autophagy is a mechanism by which cells degrade damaged or unnecessary cellular components, and is known to be used by HCV during viral replication. BL-8020 inhibits the autophagy mechanism and thus reduces the ability of HCV to replicate in the human cell.

BL-8020's safety and efficacy have been demonstrated in a number of pre-clinical studies. These studies have shown that BL-8020 has a synergistic effect with other anti-HCV agents. This effect on other therapies is likely to increase their potency and reduce the numerous adverse effects often associated with these drugs by enabling utilization of lower dosages. The use of multiple therapies with different modes of action is also likely to be beneficial for patients who have developed resistance or do not respond to current treatments and is a common practice in current HCV treatment regimens.

"We are very pleased with the initiation of a clinical trial for our first anti-HCV agent, BL-8020. HCV induces a chronic infection in over one-half of individuals infected and, depending on the virus genotype, as few as 60% completely recover. In addition, current standard-of-care treatment options are lengthy and not well tolerated," stated Dr. Kinneret Savitsky, CEO of BioLineRx. "Accordingly, there is a clear need for new drugs that can increase the effectiveness of existing treatments, especially in patients who have already undergone treatment, but have previously failed to respond or relapsed. In this respect, this study would be a first step in establishing in patients the synergistic potential of BL-8020 in combination with other HCV treatments. Based on its pre-clinical results, unique mechanism of action and synergistic effect with other anti-HCV compounds, we are very hopeful that BL-8020 will indeed enhance the activity of other available Hepatitis C treatments, thereby improving Hepatitis C care. We look forward to the partial results from the Phase I/II trial expected towards the end of 2013."

"We are also excited about the initiation of the Phase I/II clinical trial with BL-8020," stated Professor Stanislas Pol from Hopital Cochin in Paris, the lead principal investigator in the study. "Preclinical results in our ex-vivo model of infected human liver slices showed a time and dose-dependent inhibitory effect on HCV replication and infectivity. We hope that this drug, especially when combined with other available Hepatitis C drugs, will improve the treatment outcome of previously non-responsive patients," said Professor Pol.

About BL-8020

BL-8020 was licensed under a worldwide, exclusive agreement from Genoscience, a French company focused on viral disease therapeutics. It was developed as an anti-viral therapy by Professor Philippe Halfon, Co-Founder and President of Genoscience and a world-renowned scientist for his work on HIV, HPV (human papilloma virus causing cervical cancer) and Hepatitis.

About Hepatitis C

Hepatitis C infection is a blood-borne infection of the liver caused by the Hepatitis C virus (HCV) which becomes chronic in about 85% of cases. According to a 2011 report from Decision Resources, about 180 million people worldwide are chronically infected with HCV. In addition, HCV infection is the leading cause of liver transplantation and is a risk factor for liver cancer. The global Hepatitis market was estimated at $6 billion in 2011 and is forecasted to grow to $20 billion by the end of the decade.

About BioLineRx

BioLineRx is a publicly-traded biopharmaceutical development company. BioLineRx is dedicated to building a portfolio of products for unmet medical needs or with advantages over currently available therapies. BioLineRx's current portfolio consists of seven clinical stage candidates: BL-1040, for prevention of pathological cardiac remodeling following a myocardial infarction, which has been out-licensed to Ikaria Inc., is currently undergoing a pivotal CE-Mark registration trial; BL-5010 for non-surgical removal of skin lesions has completed a Phase I/II study; BL-7040 for treating inflammatory bowel disease (IBD) has completed a Phase IIa trial; BL-8040 for treating acute myeloid leukemia (AML) and other hematological cancers will shortly commence a Phase II study; BL-1021 for neuropathic pain is in Phase I development; BL-8020 for hepatitis C (HCV) is commencing a Phase I/II study; and BL-1020 for schizophrenia. In addition, BioLineRx has five products in various pre-clinical development stages for a variety of indications, including central nervous system diseases, infectious diseases, cardiovascular and autoimmune diseases.

BioLineRx's business model is based on acquiring molecules mainly from biotechnological incubators and academic institutions. The Company performs feasibility assessment studies and development through pre-clinical and clinical stages, with partial funding from the Israeli Government's Office of the Chief Scientist (OCS). The final stage includes partnering with medium and large pharmaceutical companies for advanced clinical development (Phase III) and commercialization. For more information on BioLineRx, please visit www.biolinerx.com, the content of which does not form a part of this press release.

Various statements in this release concerning BioLineRx's future expectations, including specifically those related to the development and commercialization of BL-8020, constitute "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. These statements include words such as "may," "expects," "anticipates," "believes," and "intends," and describe opinions about future events. These forward-looking statements involve known and unknown risks and uncertainties that may cause the actual results, performance or achievements of BioLineRx to be materially different from any future results, performance or achievements expressed or implied by such forward-looking statements. Some of these risks are: changes in relationships with collaborators; the impact of competitive products and technological changes; risks relating to the development of new products; and the ability to implement technological improvements. These and other factors are more fully discussed in the "Risk Factors" section of BioLineRx's most recent annual report on Form 20-F filed with the Securities and Exchange Commission on March 12, 2013. In addition, any forward-looking statements represent BioLineRx's views only as of the date of this release and should not be relied upon as representing its views as of any subsequent date. BioLineRx does not assume any obligation to update any forward-looking statements unless required by law.

FAIR USE NOTICE:

This site contains copyrighted material the use of which has not always been specifically authorized by the copyright owner. It is being made available in an effort to advance the understanding of Hepatitis C, New hepatitis c drugs, Related clinical trials and ongoing research, HIV/HCV coinfection, HIV/AIDS, Other factors of liver disease, and so on. It is believed that this constitutes a 'fair use' of any such copyrighted material as provided for in section 107 of the US Copyright Law. In accordance with Title 17 U.S.C. Section 107, the material on this site is distributed without profit to those who have expressed a prior interest in receiving the included information for research and educational purposes. If you wish to use copyrighted material from this site for purposes of your own that go beyond 'fair use', you must obtain permission from the copyright owner.

The material in this site is provided for educational and informational purposes only, and is not intended to be a substitute for a health care provider's consultation. Please consult your own appropriate health care provider about the applicability of any opinions or recommendations with respect to your own symptoms or medical conditions. The information on this site does not constitute medical or health related advice.